TY - JOUR
T1 - Teriflunomide and Time to Clinical Multiple Sclerosis in Patients with Radiologically Isolated Syndrome
T2 - The TERIS Randomized Clinical Trial
AU - Lebrun-Frénay, Christine
AU - Siva, Aksel
AU - Sormani, Maria Pia
AU - Landes-Chateau, Cassandre
AU - Mondot, Lydiane
AU - Bovis, Francesca
AU - Vermersch, Patrick
AU - Papeix, Caroline
AU - Thouvenot, Eric
AU - Labauge, Pierre
AU - Durand-Dubief, Françoise
AU - Efendi, Husnu
AU - Le Page, Emmanuelle
AU - Terzi, Murat
AU - Derache, Nathalie
AU - Bourre, Bertrand
AU - Hoepner, Robert
AU - Karabudak, Rana
AU - De Seze, Jérôme
AU - Ciron, Jonathan
AU - Clavelou, Pierre
AU - Wiertlewski, Sandrine
AU - Turan, Omer Faruk
AU - Yucear, Nur
AU - Cohen, Mikael
AU - Azevedo, Christina
AU - Kantarci, Orhun H.
AU - Okuda, Darin T.
AU - Pelletier, Daniel
N1 - Publisher Copyright:
© 2023 American Medical Association. All rights reserved.
PY - 2023/10/9
Y1 - 2023/10/9
N2 - Importance: Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system. Objective: To determine the time to onset of symptoms consistent with MS. Design, Setting, and Participants: From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144. Interventions: Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred. Main outcomes: Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs. Results: Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P =.02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P =.007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P =.14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P =.09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P =.54) were not significant. Conclusion and Relevance: Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum. Trial Registration: ClinicalTrials.gov Identifier: NCT03122652.
AB - Importance: Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system. Objective: To determine the time to onset of symptoms consistent with MS. Design, Setting, and Participants: From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144. Interventions: Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred. Main outcomes: Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs. Results: Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P =.02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P =.007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P =.14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P =.09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P =.54) were not significant. Conclusion and Relevance: Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum. Trial Registration: ClinicalTrials.gov Identifier: NCT03122652.
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U2 - 10.1001/jamaneurol.2023.2815
DO - 10.1001/jamaneurol.2023.2815
M3 - Article
C2 - 37603328
AN - SCOPUS:85173575421
SN - 2168-6149
VL - 80
SP - 1080
EP - 1088
JO - JAMA neurology
JF - JAMA neurology
IS - 10
ER -